Process for preparing fluorine-containing benzaldehydes

ABSTRACT

The invention relates to a particularly advantageous preparation of fluorine-containing benzaldehydes by reacting a corresponding aromatic acid chloride with hydrogen in the presence of a supported palladium catalyst and a catalyst moderator.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to a process for preparingfluorine-containing benzaldehydes by reduction of the correspondingaromatic acid chlorides.

[0002] Fluorinated benzaldehydes are important building blocks foractive compounds in the pharmaceuticals sector. They can also beconverted by reduction into the corresponding benzyl alcohols thatlikewise have a wide range of uses for active compounds in thepharmaceuticals sector.

[0003] Processes for preparing fluorine-containing benzaldehydes areknown. Thus, fluorinated benzoyl chlorides are reduced to thecorresponding benzaldehydes by a Rosenmund reaction (see Org. React.Vol. 4, 362) in sulfolane as solvent (EP-A 171 065). High yields areobtained in this way, but the use of a solvent means that the processhas the disadvantage of a lower space-time yield and higher materialscosts. Furthermore, especially for 3,5-bis(trifluoromethyl)benzoylchloride, increased overhydrogenation of the benzoyl chloride to thecorresponding benzene is observed.

[0004] Specifically for the preparation of3,5-bis(trifluoromethyl)benzaldehyde, there are many known syntheticroutes that are not all suitable for a preparation on a relatively largescale. Thus, the corresponding bromobenzene has been reacted withbutyllithium and N,N-dimethyl-formamide (J. Med. Chem. 16, 1399 (1973)and Chem. Ber. 129, 233 (1996)). Due to the handling of pyrophoricorganolithium compounds, this process has particularly high safetyrequirements.

[0005] The Grignard reaction of the corresponding bromobenzene withmagnesium and triethyl orthoformate (Eur. J. Med. Chem. Chim. Ther. 14,411 (1979)) has similarly high safety requirements for the handling oforganomagnesium compounds.

[0006] The industrially difficult-to-obtain3,5-bis(trifluoromethyl)benzyl alcohol has also been oxidized withpyridinium dichromate in moderate yield (J. Amer. Chem. Soc. 107, 2442(1985)). This produces toxic chromium-containing waste that requirescostly disposal.

[0007] A Stephen reduction of the corresponding nitrile using tin(II)chloride/hydrogen chloride gas (J. Chem. Soc. Perkin Trans. 2,1987, 639)gives stoichiometric amounts of toxic tin salts as waste product.

[0008] Reduction of benzoyl chloride by means oftri-tert-butoxy-lithium-aluminum hydride in diglyme has also beendescribed (J. Med. Chem. 15, 775 (1972)). However, aluminum hydrides canattack trifluoromethyl groups. A further disadvantage is the formationof stoichiometric amounts of aluminum salts that must be disposed of.

SUMMARY OF THE INVENTION

[0009] We have now found a process for preparing fluorine-containingbenzaldehydes of the formula

[0010] wherein

[0011] n represents 1 or 2, and

[0012] R¹, R², and R³ each represent, independently of one another,hydrogen, fluorine, chlorine, bromine, C₁-C₆-alkyl, C₁-C₆-fluoroalkyl,C₁-C₆-fluoroalkoxy, or C₁-C₆-fluoroalkylthio, where at least one of theradicals R¹ to R³ represents fluorine or a fluorine-containing radicaland not more than two of the radicals R¹ to R³ represents bromine,C₁-C₆-fluoroalkoxy, and/or C₁-C₆-fluoroalkylthio,

[0013] comprising reacting an aromatic acid chloride of the formula

[0014] where R¹, R², R³, and n are as defined for formula (I), withhydrogen in the presence of a supported palladium catalyst and acatalyst moderator.

[0015] If the radicals R¹ to R³ are C₁-C₆-fluoroalkyl,C₁-C₆-fluoroalkoxy, or C₁-C₆-fluoroalkylthio, they can bemonofluorinated, polyfluorinated, or perfluorinated C₁-C₆-alkylthio,C₁-C₆-alkoxythio, or C₁-C₆-fluoroalkylthio radicals.

[0016] The radicals R¹ to R³ preferably each represent, independently ofone another, H, F, Cl, Br, CH₃, C₂H₅, CF₃, CF₂CH₃, C₂F₅, OCF₃, or SCF₃,where at least one of the radicals R¹ to R⁴ represents F, CF₃, CF₂CH₃,C₂F₅, OCF₃, or SCF₃ and not more than one of the radicals R¹ to R₄represents bromine, OCF₃, or SCF₃.

[0017] If the radicals R¹ to R³ are different from hydrogen and only oneCOCI group is present, they are preferably located in the 3, 4, and 5position(s) of the benzene ring relative to the COCI group.

[0018] Particular preference is given to using mono-, di-, andtrifluorobenzoyl chlorides, mono- and bis-trifluoromethylbenzoylchlorides, monotrifluoromethoxybenzoyl chlorides, and monochloro- andmonobromotrifluoromethylbenzoyl chlorides in the process of theinvention for preparing the corresponding fluorine-containingbenzaldehydes.

[0019] The hydrogen can be employed, for example, at pressures in therange from 0.5 to 3 bar. It is preferably employed under atmosphericpressure. The hydrogen gas can be passed into the reaction mixture bymeans of, for example, a tube or a frit. The hydrogen gas can also bepassed into the space above the mixture. The hydrogen gas is preferablypassed into the reaction mixture.

[0020] Suitable support materials for the supported palladium catalystare, for example, carbon, aluminum oxides, silicates, silica, and bariumsulfate. Preference is given to carbon and barium sulfate. The supportedpalladium catalysts can contain, for example, from 1 to 10% by weight ofpalladium. The weight ratio of supported palladium catalyst to thearomatic acid chloride used can be, for example, from 1:2 to 1:1000(preferably from 1:5 to 1:500).

[0021] Suitable catalyst moderators are, for example, organic sulfurcompounds. Preference is given to thiophenol, thioanisole, thiourea,sulfolane, and quinoline-sulfur complexes. Particular preference isgiven to quinoline-sulfur complexes as described, for example, in Org.Reactions, Vol. 4, 362, or can be obtained as described in the presentExample 1 or by methods analogous thereto.

[0022] The weight ratio of catalyst moderator to supported palladiumcatalyst can be, for example, from 1:1 to 1:500 (preferably from 1:10 to1:200).

[0023] The catalyst moderator can, for example, be initially chargedtogether with the aromatic acid chloride and the catalyst. It is alsopossible for the supported palladium catalyst to be brought into contactwith the catalyst moderator first, optionally in the presence of anauxiliary, and for the catalyst/moderator combination then to be used inthe process of the invention.

[0024] After the reaction is complete, the catalyst can be separatedoff, e.g., by filtration, and reused in the next batch. This reuse canbe repeated up to 5 or more times. Reused catalysts can generally beused without further addition of catalyst moderator.

[0025] The auxiliary can be, for example, a small amount of an aromatichydrocarbon, a halogenated hydrocarbon, a halogenoaromatic, an aproticamide, an acyclic or cyclic ether, or a sulfone. For the purposes of thepresent invention, the term “a small amount” is, for example, an amountof up to 2.5 ml per 100 g (preferably from 0.02 to 0.5 ml per 100 g) ofaromatic acid chloride used.

[0026] The auxiliary can not only serve to improve contact between thesupported palladium catalyst and the catalyst moderator, but also, forexample, for slurrying a supported palladium catalyst already containingcatalyst moderator before the addition of the aromatic acid chloride.

[0027] The reaction of the invention is carried out at temperatures atwhich the starting material is liquid, for example, at temperatures inthe range from 20 to 200° C. If a starting material has a melting pointabove 20° C., the melting point of the starting material is the lowestsuitable reaction temperature. If a starting material boils at below200° C. under atmospheric pressure, the reaction may be carried outunder superatmospheric pressure so that the starting material remains inthe liquid state. It is also advantageous to carry out the reaction ofthe invention at temperatures and pressures at which the respectiveproduct is liquid. In general, the reaction can be carried out attemperatures in the range from 70 to 130° C. at atmospheric pressure.Particularly preferred reaction temperatures are in the range from 80 to120° C.

[0028] The reaction of the invention can be carried out, for example, byinitially charging an aromatic acid chloride, a supported palladiumcatalyst containing a catalyst moderator, and optionally a small amountof auxiliary and setting the reaction conditions while introducinghydrogen. It is also possible for an aromatic acid chloride, a supportedpalladium catalyst, a catalyst moderator, and optionally a small amountof auxiliary to be initially charged and the reaction conditions to beset while introducing hydrogen.

[0029] The reaction is complete when the offgases from the reaction nolonger have an acidic reaction. The workup of the reaction mixture,optionally after cooling and depressurization, can be carried out invarious ways, for example, by distilling the fluorine-containingbenzaldehyde prepared directly from the reaction mixture, optionallyunder reduced pressure.

[0030] It is also possible for the catalyst to be separated off first,e.g., by filtration, and the product then to be isolated from thefiltrate by distillation, optionally under reduced pressure. In thiscase, a small amount of over-hydrogenated product (i.e., benzenederivative) and/or a small amount of any auxiliary used may be obtainedas first fraction.

[0031] It is frequently also possible for the crude product obtainedafter separating off the catalyst to be used further as such, e.g., forpreparing fluorinated benzyl alcohols by reduction.

[0032] The process of the invention makes it possible to preparefluorinated benzaldehydes of the formula (I) in higher space-timeyields, without solvent and with less overhydrogenation to the benzenestage than hitherto, with no toxic waste being obtained and noparticular safety measures being necessary.

[0033] The following examples further illustrate details for the processof this invention. The invention, which is set forth in the foregoingdisclosure, is not to be limited either in spirit or scope by theseexamples. Those skilled in the art will readily understand that knownvariations of the conditions of the following procedures can be used.Unless otherwise noted, all temperatures are degrees Celsius and allpercentages are percentages by weight.

EXAMPLES Example 1

[0034] 60 g of freshly distilled quinoline and 10 g of sulfur wererefluxed for 5 hours with stirring. The cooled mixture was diluted with700 ml of toluene. This gave a solution of a quinoline-sulfur complexcontaining 100 mg of the complex per ml. 2.5 g of 5% palladium on bariumsulfate, 0.25 ml of the solution of the complex and 250 g of

[0035] 3,5-bis(trifluoromethyl)benzoyl chloride were placed in areaction vessel at room temperature with exclusion of water. A gentlestream of hydrogen gas was then passed through the mixture atatmospheric pressure. The mixture was subsequently heated to 100-110° C.and hydrogen gas was continuously introduced at atmospheric pressure.After liberation of acidic offgases had ceased (12 hours), the mixturewas cooled, the catalyst was separated off by filtration, and thefiltrate was distilled at 27 mbar. A yield of 190.0 g of3,5-bis(trifluoromethyl)benzaldehyde having a boiling point of 79° C.was obtained. This corresponds to a yield of 86% of theory. A smallamount of a mixture of toluene and 3,5-bis(trifluoromethyl)benzene wasobtained as first fraction during the distillation.

Example 2

[0036] 1 g of 5% palladium on barium sulfate (recovered from Example 1)and 100 g of 4-trifluoromethylbenzoyl chloride were placed in a reactionvessel at room temperature with exclusion of water. A gentle stream ofhydrogen gas was then introduced at atmospheric pressure. The mixturewas subsequently heated to 100-110° C. and hydrogen gas was introducedcontinuously at atmospheric pressure. After liberation of acidicoffgases had ceased (6.5 hours), the mixture was cooled to roomtemperature, the catalyst was removed by filtration, and the filtratewas distilled at 33 mbar. At a boiling point of 82-86° C.,4-trifluoromethylbenzaldehyde was obtained in a yield of 45.9 g. Thiscorresponds to a yield of 54% of theory.

Example 3

[0037] 0.5 g of 5% palladium on barium sulfate (recovered fromExample 1) and 48 g of 3-bromo-4-trifluoromethoxybenzoyl chloride wereplaced in a reaction vessel at room temperature with exclusion of water.A gentle stream of hydrogen gas was then introduced at atmosphericpressure. The mixture was subsequently heated to 100-110° C. andhydrogen gas was introduced continuously at atmospheric pressure. Afterliberation of acidic offgases had ceased (11 hours), the mixture wascooled to room temperature, the catalyst was removed by filtration andthe filtrate was distilled at 25 mbar. At a boiling point of 112° C.,3-bromo-4-trifluoromethoxybenzaldehyde was obtained in a yield of 31.3g. This corresponds to a yield of 74% of theory.

Example 4

[0038] 0.5 g of 5% palladium on barium sulfate (recovered fromExample 1) and 50 g of 3-fluorobenzoyl chloride were placed in areaction vessel at room temperature with exclusion of water. A gentlestream of hydrogen gas was then introduced at atmospheric pressure. Themixture was subsequently heated to 80-90° C. and hydrogen gas wasintroduced continuously at atmospheric pressure. After liberation ofacidic offgases had ceased (9.5 hours), the mixture was cooled to roomtemperature, the catalyst was removed by filtration and the filtrate wasdistilled at 28 mbar. At a boiling point of 73° C., 3-fluorobenzaldehydewas obtained in a yield of 23.0 g. This corresponds to a yield of 57% oftheory.

Example 5

[0039] (not according to the invention)

[0040] 37 g of 3,5-bis(trifluoromethyl)benzaldehyde and 4 g of Raneynickel together with 150 ml of toluene were placed in a reaction vesselat room temperature. The vessel was pressurized with 30 bar of hydrogengas and the mixture was hydrogenated at 50° C. for 7.5 hours whilestirring. The mixture was subsequently cooled to room temperature,depressurized and the catalyst was filtered off. The filtrate wasevaporated and the crude product obtained in this way was distilled at17 mbar. 3,5-bis(trifluoromethyl)benzyl alcohol having a boiling pointof 97° C. was obtained in a yield of 31.5 g and a purity of 97.7%. Thiscorresponds to a yield of 82.5% of theory.

What is claimed is:
 1. A process for preparing fluorine-containingbenzaldehydes of the formula

wherein n represents 1 or 2, and R¹, R², and R³ each represent,independently of one another, hydrogen, fluorine, chlorine, bromine,C₁-C₆-alkyl, C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, orC₁-C₆-fluoroalkylthio, where at least one of the radicals R¹ to R³represents fluorine or a fluorine-containing radical and not more thantwo of the radicals R¹ to R³ represents bromine, C₁-C₆-fluoroalkoxy,and/or C₁-C₆-fluoroalkylthio, comprising reacting an aromatic acidchloride of the formula

where R¹, R², R³, and n are as defined for formula (I), with hydrogen inthe presence of a supported palladium catalyst and a catalyst moderator.2. A process according to claim 1 wherein the radicals R¹ to R³ eachrepresent, independently of one another, H, F, Cl, Br, CH₃, C₂H₅, CF₃,CF₂CH₃, C₂F₅, OCF₃, or SCF₃, where at least one of the radicals R¹ to R³represents F, CF₃, CF₂CH₃, C₂F₅, OCF₃, or SCF₃ and not more than one ofthe radicals R¹ to R³ represents bromine.
 3. A process according toclaim 1 wherein the hydrogen is employed at a pressure in the range from0.5 to 3 bar and a reaction temperature of from 20 to 200° C.
 4. Aprocess according to claim 1 wherein the supported palladium catalystcomprises from 1 to 10% by weight of palladium and carbon, aluminumoxides, silicates, silicas, or barium sulfate as a support material . 5.A process according to claim 1 wherein the weight ratio of the supportedpalladium catalyst to the aromatic acid chloride is from 1:2 to 1:1000.6. A process according to claim 1 wherein the catalyst moderatorcomprises organic sulfur compounds.
 7. A process according to claim 1wherein the weight ratio of catalyst moderator to the supportedpalladium catalyst is from 1:1 to 1:500.
 8. A process according to claim1 wherein the catalyst is separated off after the reaction is completeand is reused without further addition of catalyst moderator.
 9. Aprocess according to claim 1 wherein 0 to 2.5 ml, per 100 g of thearomatic acid chloride, of an aromatic hydrocarbon, a halogenatedhydrocarbon, a halogenoaromatic, an aprotic amide, an acyclic or cyclicether, or a sulfone are used as an auxiliary.
 10. A process according toclaim 1 wherein the fluorine-containing benzaldehyde is isolated afterthe reaction is complete by distillation, optionally under reducedpressure and optionally after the catalyst has first been separated.